Action Points

Explain to interested patients that aromatase inhibitors and tamoxifen alike work to suppress estrogen in the body and thereby reduce the risk of breast cancer recurrence.

Note that this study was published as an abstract and presented orally at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

SAN ANTONIO, Dec. 12 -- Whether breast cancer patients start on adjuvant aromatase inhibitors, or switch to them later, they lead to a lower risk of recurrence than tamoxifen, and, for some, better survival, researchers said here.

In a meta-analysis across agents, five years on an aromatase inhibitor reduced recurrence an absolute 2.9% with a nonsignificant 1.1% absolute reduction in breast cancer mortality compared with tamoxifen, James Ingle, M.D., of the Mayo Clinic in Rochester, Minn., and colleagues reported at the San Antonio Breast Cancer Symposium.

Women who switched to an aromatase inhibitor after two or three years of tamoxifen had a 29% proportional reduction in recurrence and a significant 0.7% absolute reduction in breast cancer mortality three years later compared with women who stayed on tamoxifen.

"It does not appear that there's any subset of patients who don't get benefit from the aromatase inhibitors," Dr. Ingle said.

These findings summing up the worldwide prospective experience comparing the two classes of endocrine therapy should erase any doubts that aromatase inhibitors are the "somewhat better" choice, he said.

Even though the individual trials seem large enough to answer questions on their own, tamoxifen-treated patients do so well that it takes very large studies, such as the meta-analysis, to get enough events to properly power subgroup analyses, added co-author Mitch Dowsett, Ph.D., of the Royal Mardsen Hospital in London.

So their group pooled data from all trials started by 2000, prospectively comparing an aromatase inhibitor and tamoxifen. Unpublished data from the ABCSG VIII and BIG 1-98 trials were not included.

Among the 9,856 patients who received therapy in trials directly comparing five years of monotherapy, recurrence rates were uniformly lower with aromatase inhibitors.

Aromatase inhibitors were associated with an absolute 2.9% lower recurrence rate at five years that improved to a 3.9% gain at eight years (15.3% versus 19.2%, P<0.00001).

The annual event rate ratios revealed the following compared with tamoxifen:

23% reduction in any recurrence (P<0.00001)

30% lower rate of isolated local recurrence (P=0.003)

41% reduction in isolated contralateral recurrence (P=0.0009)

16% reduced distant recurrence rate (P=0.009)

18% lower rate of any distant recurrence (P=0.002)

Mortality analyses showed small, nonsignificant advantages to five years of aromatase monotherapy with gains of 1.1% and 0.5% for five- and eight-year breast cancer mortality and 0.8% and 0.2% gains, respectively, for all-cause mortality.

Dr. Ingle noted that the mortality data were still relatively early with a mean follow-up of 3.9 years. He also noted that tamoxifen's survival advantage at five years was only one-third of what it was at 15 years.

For the 9,015 patients in the pooled analyses comparing tamoxifen monotherapy and two to three years of tamoxifen followed by two to three years aromatase inhibitor, recurrence again was uniformly significantly superior for the group that switched.

These findings included 29% lower overall annual recurrence event rates (P<0.00001) with an absolute gain of 3.1% at three years after the switch and 3.5% at six years after switching (P<0.00001).

The switch cohort showed absolute benefits in the following mortality outcomes as well:

0.7% lower breast cancer mortality at three years and 1.6% at six years (P=0.02)

0.4% lower rates of death without recurrence at three years and 0.7% at six years (P=0.08)

1.1% lower all-cause mortality at three years and 2.2% at six years (P=0.004)

The reason for the difference in mortality benefits between cohorts might have been because some patients about ready to progress on tamoxifen were salvaged when they switched to an aromatase inhibitor, Dr. Ingle suggested.

The advantage of aromatase inhibitors over tamoxifen fell over time in both cohorts, which he said highlights the major remaining question with these agents -- duration of adjuvant therapy.

But all age, nodal status, and tumor grade subgroups showed benefits. The only factor with significant heterogeneity was progesterone receptor status in the monotherapy cohort, which Dr. Ingle said could have been a chance finding.

Dr. Ingle reported no conflicts of interest. Dr. Dowsett reported conflicts of interest for Novartis and AstraZeneca. Co-authors also reported conflicts of interest for AstraZeneca.

Reviewed by Zalman S. Agus, MD Emeritus Professor University of Pennsylvania School of Medicine

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